Risk Factors for HABP/VABP Study and Early Enrollment Study
Clinical trials to evaluate the efficacy and safety of new antibacterial drugs for hospital-acquired and ventilator-associated bacterial pneumonia (HABP/VABP) are challenging to conduct and expensive, yet critically needed. CTTI is gathering evidence that will lead to improved feasibility of HABP/VABP clinical trials.
After assembling a network of sites as part of the Streamlining HABP/VABP Trials Project, CTTI conducted a prospective, multi-center, observational study of the risk factors for HABP/VABP. Additional adult sites were added in Europe through a collaboration with COMBACTE CLIN-Net and a pediatric arm of the study was conducted by the Pediatric Trials Network. Over 6,700 adult patients were enrolled at 28 US sites and seven European sites. In addition, 800 pediatric patients were enrolled at nine U.S. children’s hospitals. These data will improve understanding of the risk factors associated with HABP/VABP development and inform clinical trial planning. For example, patients at high risk for developing pneumonia could be approached and consented early, many before pneumonia symptoms develop, so that fewer patients are excluded because they have already received 24 hours of effective antibacterial therapy.
One of the challenges in planning the HABP/VABP pilot study is determining which patients to approach for early enrollment. A group of patients at risk for pneumonia is required, but selecting criteria based on existing literature will involve a tradeoff between sensitivity and specificity. Approaching only the highest risk patients (e.g., those on a ventilator for a pre-specified length of time) would likely yield a relatively high percentage of patients who go on to develop pneumonia. The drawbacks of this approach include 1) not including a mix of VABP and non-VABP HABP; 2) exclusion of a large group of other patients who go on to develop pneumonia in the hospital in absence of the highest risk factors; and 3) increased likelihood of exclusion due to current use of antibiotics. Using a more inclusive approach, such as enrolling patients with a history of aspiration or with chronic lung disease, would increase the total number of patients who ultimately develop pneumonia, but would decrease the proportion of enrolled patients that develop pneumonia. If the proportion of patients developing pneumonia is too low, it is possible that the time, effort, and money required to conduct a study using an early enrollment strategy would not result in a meaningful increase in number of patients enrolled who ultimately meet study criteria for antibacterial therapy for HABP/VABP.
A risk factor study is being conducted to better define the population at highest risk for developing HABP/VABP. These results, in combination with CTTI’s Recommendations for Streamlining HABP/VABP Clinical Trials, which include a proposal for early consent to increase enrollment, have informed the development of an early enrollment strategy. The feasibility of the early enrollment approaches will be tested in a randomized pilot study to help drive adoption across the clinical trial enterprise.
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ABDD Program: Prospective Observational Study of the Risk Factors for Hospital-Acquired and Ventilator-Associated Bacterial Pneumonia (HABP/VABP) and Early Enrollment Study (Ongoing)
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The ABDD Program will facilitate the development of new antibacterial drugs for HABP/VABP. Specifically, CTTI’s HABP/VABP studies will provide evidence for new enrollment techniques in HABP/VABP clinical trials. Evidence that an innovative enrollment approach will work can lead to more HABP/VABP clinical trials, which will eventually lead to more available antibiotics.
The related CTTI Streamlining HABP/VABP Trials Project included a number of collaborative efforts to better understand and address the challenges of conducting HABP/VABP trials. A data gathering and mapping project conducted in collaboration with the Tufts Center for the Study of Drug Development found that the cost of screen failures, as well as screen failure rates, are the main drivers of cost for a phase 3 HABP/VABP trial. HABP/VABP phase 3 trials are generally non-inferiority trials.
To address the concern of bias toward non-inferiority, FDA Draft Guidance recommends that patients who have received effective antibacterial drug therapy for HABP/VABP for a continuous duration of more than 24 hours during the previous 72 hours be excluded from HABP/VABP clinical trials. In a guided discussion with experienced research coordinators conducted by CTTI, this recommended exclusion criteria was noted as a significant challenge to enrollment as care standards in the intensive care unit often lead to antibacterial drugs being administered as soon as pneumonia is suspected. In addition, patients are often quite ill and unable to provide informed consent themselves, so legally authorized representatives must be identified and contacted for enrollment in a clinical trial. Other necessary enrollment procedures such as laboratory tests and other procedures to meet inclusion/exclusion criteria, randomization, and obtaining study drug from the pharmacy can add to the time between administration of antibacterial drugs and study enrollment. Strategies to address these feasibility concerns while ensuring that trial interpretability will not be limited by a bias toward non-inferiority are needed.
As part of the Streamlining HABP/VABP Trials Project, CTTI identified a network of US and European sites for conducting HABP/VABP studies. A working group was convened and included key stakeholders, such as infectious diseases and pulmonary/critical care medicine experts, those experienced in designing clinical studies, and patient representatives. Site contracts were negotiated to minimize potential future delays. The network is being used to conduct a prospective observational study that examines the risk factors associated with HABP/VABP. Results from this study will inform the development of a randomized interventional pilot trial to test an early enrollment strategy that could make HABP/VABP trials more feasible. An expert meeting was held to gather input on design of the planned pilot study.
CTTI, together with the Tufts Center for the Study of Drug Development, conducted an analysis of cost drivers for phase 3 HABP/VABP trials to identify ways to make these trials more feasible. Key findings included:
|Social Science Lead||Amy Corneli||Clinical Trials Transformation Initiative|
|Team Member||Beth Evans||Duke University|
|Team Member||Carisa DeAnda||Merck & Co, Inc|
|Team Member||Daniel Rubin||Food and Drug Administration|
|Team Member||Deborah Collyar||Individual Patient/Caregiver|
|Team Member||Elizabeth Alexander||The Medicines Company|
|Team Member||Heather Cross||Duke University|
|Team Member||Helen Donnelly||Northwestern University|
|Team Member||Henri van Werkhoven||University Medical Center Utrecht|
|Team Member||John Farley||Food and Drug Administration|
|Team Member||John Powers||National Institutes of Health|
|Team Member||Jonas Santiago||Food and Drug Administration|
|Team Member||Joseph Toerner||Food and Drug Administration|
|Team Member||Joshua Thaden||Duke University|
|Team Member||Karen Fusaro||The Medicines Company|
|Team Member||Kristen Miller||Food and Drug Administration|
|Team Member||Pamela Tenaerts||Clinical Trials Transformation Initiative|
|Team Member||Peidi Gu||Duke University|
|Team Member||Rose Tiernan||Food and Drug Administration|
|Project Manager||Sara Calvert||Clinical Trials Transformation Initiative|
|Team Member||Simone Shurland||Food and Drug Administration|
|Team Member||Stephen Bergin||Duke University|
|Team Member||Thomas Holland||Duke University|
|Principal Investigator||Vance Fowler||Duke University|